The transdermal route of administration of pharmacologically active substances has been generally limited to those substances intended solely for localized action and only rarely has this route been used to obtain a systemic effect. Thus we find that the teachings of the prior art establish that the transdermal route of drum administration results in variable and ineffective blood levels for virtually all pharmacologically active substances with only a rare exception as for example nitroglycerine being administered transdermally. However, when nitroglycerine is used transdermally it is dispersed in high concentrations (20 milligrams per gram) in single phase lipophilic ointments because the limitations of these unctious preparations materially restrict their use and consequent physiologic effects.
Prior art nitroglycerine ointments are all single lipophilic systems comprising a non-polar fatty base which contrasts sharply with the complex polar composition of skin and skin secretions. The opposing properties between skin and fatty ointments result in an irregular interface contact between the topically applied single phase lipophilic ointment composition and the hydrophilic skin. The single phase lipophilic ointment tends to form an occulsive film on the skin surface which facilitates pooling of the essentially aqueous polar skin fluids to cause a discontinuity of the interface between the skin and applied ointment. The consequent irregular and variable absorption pattern diminishes the bioavailability of the active substance to render the single phase lipophilic bases generally ineffective for percutaneous administration.
To overcome the irregular absorption pattern and poor bioavailability observed with the older single phase nitroglycerine fatty ointments, greatly increasing concentrations of active ingredient have been used to force penetration to take place. This increased quantity of drug added a noxious and toxic threat to the patient because of its potency as well as burdening an already inferior dosage form with limited absorption. These limitations are readily seen when a comparison is made of the varying concentrations of nitroglycerine required for clinical use by the different routes of administration. For example, 0.15 mg/tablet is utilized for oral administration, and 0.60 mg/tablet is utilized for sublingual administration, but when nitroglycerine is administered topically in the single phase lipophilic ointment, then twenty (20) milligrams per gram are required to achieve comparable bioavailability.
The amount of nitroglycerine required to achieve the desired result percutaneously from a lipophilic ointment base is from 33 to 133 times the amount of nitroglycerine required to achieve the same affect by the sublingual and/or oral routes of administration for the same substance.
The single phase lipophilic bases of the nitroglycerine ointments of the prior art generally consist of lanolin, or lanolin and white petrolatum mixtures. These preparations are unctuous, fatty substances so that a sticky, greasy layer remains on the skin for some time after administration and stains clothes and other linens. Moreover, it is known that lanolin elicits an allergic response in some individuals (about 1%) and this is a further disadvantage to the use of the prior art ointments.
Nitroglycerine is a volatile explosive compound and is available as an article of commerce as an adsorbate on diverse carriers including glycose substance and inert mineral carriers.
Furthermore, the lactose which comprises a necessary adsorbate ingredient when nitroglycerine is used in pharmaceutical compounding, is not soluble in the single phase lipophilic systems and therefore the finished unctuous ointment preparation is gritty in both texture and appearance.